The intestine, the largest immune organ in the body

The intestine is considered as the the largest immune organ in the body.

The intestinal structure is crucial for the health and performance of animals. In addition to the digestive functions of the gastrointestinal tract (GIT), the immune cells and lymphoid structures present in the GIT constitute the largest immune organ in the body.

The foundations of the mucosal-associated immune system in the intestine are divided into five spheres, which are:

Epithelial barrier, a physical barrier composed of epithelial cell layers (enterocytes and colonocytes), mucus-producing goblet cells (goblet cells), bactericidal substance-producing Paneth cells (defensins), carrier cells (M cells), and intraepithelial T lymphocytes (Figure 1).

Isolated lymphoid follicles, site of initiation of adaptive immune responses, organized structure of immune cell populations.

Peyer’s patches, the site of initiation of adaptive immune responses, an organized structure of multiple lymphoid follicles with germinal centers.

Diffuse lymphoid tissue, macrophages, dendritic cells, mast cells, irritating T lymphocytes, regulatory T cells, IgA-secreting plasma cells scattered within the lamina propia of the mucosa.

Mesenteric lymph nodes, the site of initiation of adaptive immune responses against intestinal antigens brought by the lymphatic system (Gonçalves et al., 2016).

Figure 1. Structure of defense of the intestinal epithelial barrier (adapted from D. Artis. 2008; 8:411 Nature Reviews Immunology).

The surface of the mucosa (Figure 2) is covered with mucus formed by mucins, which are secreted by goblet cells and create a barrier that prevents larger particles, including most bacteria, from coming into direct contact with the layer of epithelial cells (Turner, 2009).

Figure 2. Representation of the intestinal mucosal epithelium.

Paneth cells (Figure 3), located in the crypts of the small intestine, secrete α-defensins. In the colon, β-defensin peptides are produced by absorptive epithelial cells in intestinal crypts, some constitutively and others in response to the proinflammatory cytokine IL-1 (Abbas et al., 2015).

The expression of regenerating islet-derived protein III gamma (REGIIIγ) by intestinal epithelial cells requires signals from Toll-like receptors (TLRs) in response to invading organisms, and its production increases after colonization and infection by pathogens (Abbas et al., 2015).

Figure 3. Paneth cell.

Immune response

The innate immune response begins with the mediation through the recognition of pathogen-associated molecular patterns (PAMPs), as well as cellular pattern recognition receptors (PRRs). Toll-like receptors (TLRs) function as PRRs in mammals and play a crucial role in recognizing microbial components and initiating the innate immune response.

TLRs are divided into two subgroups, depending on their cellular location and specificity regarding their respective PAMPs.

One group consists of TLR-1, TLR-2, TLR-4, TLR-5, TLR-6, and TLR-10, which are expressed on cell surfaces and recognize microbial membrane components such as lipids, lipoproteins, and proteins.

The other group is composed of TLR-3, TLR-7, TLR-8, and TLR-9, which are exclusively expressed in the intracellular vesicle and recognize microbial DNA (Cario, 2005).

The disruption of the integrity of the epithelial barrier, characterized by increased intestinal permeability, leads to tissue invasion by pathogenic bacteria (Figure 4), as well as an increase in intact dietary antigens in the intestinal mucosa, which in turn leads to increased synthesis of inflammatory cytokines by immune cells in the mucosa.

This reaction can trigger an immune response, which can lead to an exaggerated and pathological immune response, culminating in a process of intestinal inflammation (Gonçalves et al., 2016).

 

Figure 4. Immediate immune system response to pathogen invasion.

Under these conditions, for effective protection, the animal organism must possess defense systems that detect and eliminate invading microorganisms efficiently, preferably without causing tissue damage and discomfort, a function attributed to the adaptive immune system (Levinson, 2016).

Adaptive immune responses in the gastrointestinal tract (GIT) are initiated in discretely organized sets of lymphocytes and antigen-presenting cells closely associated with the epithelial mucosal lining of the intestine, as well as in the mesenteric lymph nodes (Abbas et al., 2015).

Organized and non-encapsulated lymphoid tissues consisting of immune cells are associated with mucosal surfaces (Figure 5) of the respiratory, gastrointestinal, and urogenital tracts, collectively referred to as MALT (Mucosa-associated lymphoid tissue).

Specifically in the mucosa of the GIT, there is the GALT system (gut-associated lymphoid tissue), which consists of dense lymphoid tissue (Gonçalves et al., 2016).

 

Figure 5. Organization of lymphoid tissues on the surface of the intestinal tract.

In GALT, lymphoid tissue is distributed along structures such as:

Mesenteric lymph nodes (LN),

Lamina propria (LP), such as Peyer’s patches (PP) in the ileum, or as more diffuse lymphoid aggregates (Vega-Lopez et al., 2012).

In addition to these structures, antigen-presenting cells (APCs), dendritic cells (DCs), macrophages, T cells, and B cell areas with germinal centers in the LP, and natural killer (NK) cells form the GALT structure (Cunha, 2013).

The most prominent GALT structures are Peyer’s patches, which are primarily found in the distal ileum, and in small aggregates of lymphoid follicles or isolated follicles in the appendix and colon.

Peyer’s patches have the structure of lymphoid follicles, with germinal centers containing B lymphocytes, follicular helper T cells, follicular dendritic cells, and macrophages. The germinal centers within the follicles are surrounded by immature follicular B cells that express IgM and IgD.

A region called the dome located between the follicles and the lining epithelium contains B and T lymphocytes, dendritic cells, and macrophages (Abbas et al., 2015).

The main pathway for antigen distribution within GALT occurs through specialized cells called microfold cells (M cells), which are found in regions of the intestinal epithelium called dome epithelium or follicle-associated epithelium (FAE) (Abbas et al., 2015).

While M cells play a crucial role in the immune response against luminal microorganisms, some pathogenic microorganisms have evolved to deceive the M cell mechanism of action, using them as a pathway for invasion through the mucosal barrier.

The best-described example is Salmonella typhimurium, similar to the human pathogen S. typhi, which causes typhoid fever. M cells express lectins that allow specific binding and internalization of these bacteria.

Bacteria are cytotoxic to M cells, leading to increased intestinal permeability (Figure 6) and subsequently the proliferation of microorganisms (Abbas et al., 2015).

Figure 6. Some pathogens use M cells as a pathway for invasion through the mucosa. Subsequently, other defense cells come into action.

Dendritic cells and macrophages are sentinel cells and antigen processors; as a result, antigen processing can be initiated simultaneously with the elimination of the invader by innate defenses.

After phagocytosis, the invading microorganisms will be processed intracellularly and fragmented into smaller peptides, which will then bind to specialized antigen-presenting receptors called major histocompatibility complex (MHC) molecules and be transported to the cell surface, so that the triggering of adaptive immunity occurs when these MHC-bound peptides are recognized by specific receptors on lymphocytes (Tizard, 2008).

In view of the above, it is evident that the intestine, in addition to being an organ responsible for the processes of digestion and nutrient absorption, plays a crucial role in the defense and immune response of the body. Thus, the maintenance of intestinal health will be reflected in the health and productive performance of animals.

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